New 6-aminopenicillanic acid derivatives



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Patent @fnitc g Patented Nov. 7, 1961 a a animals. Thus, approximately 60% of an orally admin NEW aAMlNgyENiCfiLLAmqj ACE) stered dose of our compounds can be shown to be present DERWATHVE n tne urine of the treated annnal so: hours aiter adnun- Hubert Vauderhaeghe, fiaint-Giiles-Brussels, Michel (liaelstratlon whereas only some 25% 1161119111111 V can be i Hgveflgg, d P l V m and G i 5 shown to be present under similar circumstances. By virinenticr, Louvain, Belgium, assignors to Recherche ct tue of this property, the compounds of our invention are lmi'dsme Tilemllem'iqilesp g o Gem?! lighly valuable for specific treatment of various infec- Belgiuin, a corporation of helgiurn No Drawing. Filed Feb. Zll, 61, $81. No. tl,243 Claims priority, application Great Britain Get. 28, 15363 tions of the kidneys and urogenital tract, as for example, cystitis, prostatitis, pyelitis and miscellaneous other in- 3 maims (6L zamzwl) l0 iections of the urinary tract. The compounds of our invention may be administered alone or 111 COIllllliCilOIl This invention relates to a novel class of antimicrobial With other therapeutic agents, Such as for xample, 8111* agents. More specifically, our invention pertains to novel fiSOXaZOk, sulffimeihialflle, melhenamifle mandelate,

derivatives of 6-aminopenicillanic acid which possesss phenylazodiaminopy-ridine, chloromycetin, nitrofurantoin, new and unexpected antimicrobial and physiological 5 and h like.

properties. While more preferably administered via the oral route,

I ti l th Compounds f our invgnficn may b our compounds are also suitable for injection or topical represented by the following structural formula: pp cation. They may be administered in any of the X usual pharmaceutical forms such as tablets, capsules,

; 0 s on; powders, suspension, solution, suppositories and the like.

g i In general, the compounds of our invention may be I l l I prepared by treating 6-aminopenicillanic acid with the ap- 0 CH3 (fi-N-CHC O 0111'. propriately chlorinated ot-methoxyphenylacetyl chloride or alternatively by treating 6-an1inopenicillanic acid With a wherein X represents chloro or hydrogen, and M repremixed anhydride of the chlorinated wmethoxyphenylacetic scnts hydrogen or pharmaceutically acceptable cations. acid. These reactions may be represented as follows:

0 o ll SO C19 ll 01- CH-o0H 01 CH-CC1 $0113 ($6113 I II /S\ /CI'I3 f NHz(|'JHC1I1 CCH: ClO OCzHJ C-NCH-OOOH (GMAPA) o o o s OH; H II 6-APA ll c1- (|3HC-OGOC2Hs-- o1- CHGNH-ClHCIl-I (ID-CH;

OCH; H; C-N---CHCOOl-I 0 1v III We have discovered that com ounds in this class The compounds of our invention contain an asym- P l I demonstrate an antimicrobial activity comparable to metncai carbon atom in the chlorinated x-1116th0Xypenicillin V and phenetliicillin. In addition these comp enylacetic fragment of their formulas; the epimers may pounds demonstrate certain improved physiological propbe obtalned either by optical resolution or by using optierties. In particular, our compound exhibits prolonged 5Q Cally 2 5 serum levels with increased anti-infective titers as com- A150 l'Ilclllded m the Scope of mventloll are 316 pared with penicillin v or phenethicillin. Thus not only Pharmawutwally acceptable salts of our novel p do these compounds manifest a greater anti-infective sllch as the i Salts as for p the Sodlum, P activity against those organisms susceptible to penicillin Slum and 0516mm Salts and 31111116 Salts $11911 as the V, penicillin G and phenethicillin such as Streptococcus ethylamlne, PF P p i and the Saltsand Pneutnococcus. but in addition exhibit this activity The followmfs mp W111 Serve t0 further YP Y the for a Omaha. Imam of time nature of our invention but should not be construed as A. v v a Furthermore the compounds of this invention exhibit L g i fisfi fig the scope being defined Only the unexpected and highly desirable features of rapid oral y e ppvn a absorption and resistance to degradation Within the in Example 1 69933 animals body- Hence: not only are our 6-arninopenicillanic acid (2.16 g.) is dissolved in 20 pounds elfective when administered via the oral route, but 1 f a molar aqueous solution f pgtassium b in addition largely eXcfeied in IloIl-degmdated form carbonate and 10 m1. of acetone. The resultant solution This property is manifested by the presence of a high is cooled in an ice-Water bath and to it is added with concentration of the compounds in the urine of the stirring a solution of 2.7 g. of a-n1ethoxy-3 ,4-dichlorophenylacetyl chloride in 10 m1. of acetone. The pH is adjusted to 7-8 and upon completion of the addition the reaction medium is stirred for 15 minutes at ice bath temperature and then for 2% hours at room temperature, maintaining the pH range between 7 and 8. The solution is extracted once with ether and then adjusted to pH 2.5 with 20% phosphoric acid. The acidic solution is extracted once with 30 ml. of butyl acetate and again with 10 ml. of butyl acetate. These combined butyl acetate extracts are thereafter successively washed twice with water and re-extracted at pH 7 with 0.5 N aqueous potassium hydroxide solution. The aqueous layer is Washed twice with ether and the remaining organic solvent is then removed by evaporation under reduced pressure.

The washed aqueous layer is then lyophilized and the residue thus obtained taken up in acetone. The crystalline product is collected by filtration and dried to yield the potassium salt of 6-(a-methoxy-3,4-dichlorophenylacetamido)-penicillanic acid.

Upon treatment with mineral acid of an aqueous solution of the compound so prepared, there is obtained the free acid, 6-(ct-methoxy-3,4-diohlorophenylacetamido)- penicillanic acid.

Example 2 A solution of 19.2 g. (0.096 mole) of a-methoxy-4- chlorophenyl acetic acid in 200 ml. of acetone is cooled in an ice bath to To the cooled solution is added 10.2 g. (0.1 mole) of triethylamine in 100 ml. of acetone. The temperature of the reaction mixture is maintained at 10 and a solution of 11 g. (0.1 mole) of ethylchloroformate in 45 ml. of acetone is added dropwise with agitation so as to maintain a final reaction temperature of 5. To this mixture is then slowly added with stirring a solution of 23.8 :g. (0.11 mole) of 6-aminopenicillaric acid in 40 ml. of water and 15 ml. of triethylamine. Upon completion of the addition, the mixture is stirred while attaining room temperature and then stirred for an additional one-half hour. The mixture is extracted with three portions or" 300 ml. of ether and the resulting aqueous solution adjusted to pH 2.0 with 6 N sulfuric acid, maintaining a temperature of less than 10. At pH 2, the solution is extracted with 250 ml. of butyl acetate and then extracted twice with 75 ml. each of butyl acetate. To the combined butyl acetate extracts are added 250 ml. or" water and the pH adjusted to 8.0 by the addition of sodium bicarbonate. The layers are separated and the aqueous layer adjusted to 2.0 by the addition of 6 N sulfuric acid at less than 10 C. This acid aqueous mixture is next extracted with 200 ml. of butyl acetate and the organic extract extracted once with water and dried over sodium sulfate. To the butyl acetate solution is added with vigorous stirring a solution of potassium hydroxide in n-butanol (40 g./l.) until the pH of the reaction mixture is 8.4. The mixture is then cooled until crystallization occurs. The crystals are collected by centrifugation, washed with a small amount of acetone and dried. These dried crystals are recrystallized from butanol and redried to yield 6-(a-methoxy-4-chlorophenylaoetamido)- penicillanic acid as the potassium salt.

Treatment with acid as described in Example 1 then yields the corresponding free acid 6-(e-methoxy-4-chlorophenylacetamido)-penicillanic acid.

Alternatively :x-methoxy-4-chlorophenyl acetic acid is treated with thionyl chloride to folm the corresponding acid chloride, which when substituted for a-methoxy-3,4 dichlorophenyl acetic acid to the procedure of Example 1, yields the compound 6-(a-methoxy-4-chlorophenylacetamido)-penicillanic acid.

Example 3 One gram of 6-(a-methoxy-3,4-dichlorophenylacetamido)-penicillanic acid is dissolved in excess amyl acetate and to this solution is added 0.260 g. of N-ethylpiperidine. The solution is stirred for 30 minutes and the crystals formed upon standing are collected by filtration and dried to yield the N-ethylpiperidine salt of 6-(u-methoxy-3,4- dichlorophenylacetamido) -penicilllanic acid.

Example 4 wherein X is a member selected from the group consistmg of hydrogen and chloro, and the sodium, potassium, calcium, and pharmaceutically acceptable non-toxic amine salts thereof.

2. A compound having the formula:

I CH3 0on3 C-N-CH-COOH o 3. A compound having the formula:

References Cited in the file of this patent UNITED STATES PATENTS 2,941,995 Doyle et al. June 21, 1960 FOREIGN PATENTS 569,728 Belgium Nov. 15, 1958 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ACIDS HAVING THE FORMULA: 